Process for making spirolactone compounds

ABSTRACT

This invention relates to processes for making spirolactone compounds analogous to formula I:

BACKGROUND OF THE INVENTION

[0001] This invention relates to processes for making spirolactonecompounds of formula I. The process involves ortho lithiation of anaromatic compound followed by subsequent addition to a ketonederivative. After acidification, the desired spirolactone derivative isisolated in good yield. A stereoselective reduction of the ketoneintermediate generates the desired cis isomer of the alcohol which issubsequently activated and treated with cyanide to form the desirednitrile intermediate. Hydrolysis of the nitrile under acidic conditionsselectively generates the trans carboxylic acid product. Crystallizationof the carboxylic acid intermediate gives the desired material in highlypure form.

SUMMARY OF THE INVENTION

[0002] By this invention, there is provided a process for thepreparation of a compound of structural formula I:

[0003] comprising the steps of:

[0004] a. Combining a strong base with phenyl isonicotinamide in anaprotic solvent;

[0005] b. Adding a protected ketone;

[0006] c. Adjusting the pH with an acid to between 1 and 4 to deprotectthe ketone;

[0007] d. Treating the ketone with a reducing agent to provide analcohol;

[0008] e. Activating the alcohol to make a leaving group;

[0009] f. Displacing the leaving group with cyanide to produce anitrile;

[0010] g.Hydrolyzing the nitrile with aqueous acid to yield the compoundof formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0011] By this invention, there is provided a process for thepreparation of a compound of structural formula I:

[0012] comprising combining a strong base with phenyl isonicotinamide inan aprotic solvent.

[0013] A variety of strong bases can be used in the present invention.In one class of the invention, the strong bases include, but are notlimited to n-BuLi, sec-BuLi, t-BuLi, LiHMDS, NaHMDS, KHMDS and LiTMP. Ina subclass of the invention, the strong base is n-BuLi.

[0014] Various aprotic solvents can be used in the present invention. Inone class of the invention, the aprotic solvents include, but are notlimited to THF, toluene, heptane, dimethoxyethane, benzene, and hexane,diethyl ether, xylene, and any mixtures thereof. In a subclass of theinvention the aprotic solvent is THF.

[0015] In one class of the invention, the combination of the strong baseand the phenyl isonicotinamide, and the addition of the ketoneprotecting group are run between −78° C. and 0° C.

[0016] The invention is also directed to a process comprising adding aprotected ketone after combining a compound of formula I with a strongbase and phenyl isonicotinamide in an aprotic solvent.

[0017] In one class of the invention, the protected ketone includes, butis not limited to 1,4-cyclohexanedione-mono-ethylene ketal, dimethylketal, diethyl ketal, or 1,3 dithiane, and olefin.

[0018] The invention is also directed to a process comprising adjustingthe pH with an acid to between 1 and 4 to deprotect the ketone.

[0019] In one class of the invention, the pH range includes, but are notlimited to 2-3. In a subclass of the invention, the pH is 2.40.

[0020] In one class of the invention, the acids used to lower the pHinclude, but are not limited to hydrochloric, sulfuric, phosphoric, ortriflic.

[0021] The invention is also directed to a process comprising treatingthe ketone with a reducing agent to provide an alcohol.

[0022] In one class of the invention, the reducing agent includes, butis not limited to sodium borohydride, lithium aluminum hydride, orDIBAL. In another class of the invention, the ketone may be reduced viacatalytic hydrogenation.

[0023] The invention is also directed to a process comprising activatingthe alcohol to make a leaving group. By activating the alcohol, thealcohol is converted into a leaving group at that carbon.

[0024] In one class of the invention, the leaving group includes, but isnot limited to mesylate, tosylate, triflate, and halide.

[0025] The invention is also directed to a process comprising displacingthe leaving group with cyanide to produce a nitrite.

[0026] In one class of the invention the cyanide is selected from thegroup consisting of sodium cyanide, KCN, ZnCN₂, and TMSCN.

[0027] The invention is also directed to a process comprisinghydrolyzing the nitrite with aqueous acid to produce the compound offormula I. The hydrolyzation liberates the free acid.

[0028] In one class of the invention, the aqueous acid includes, but isnot limited to sulfuric, hydrochloric, phosphoric, and any mixturesthereof.

[0029] In the schemes and examples below, various reagent symbols andabbreviations have the following meanings: n-BuLi: n-Butyl LithiumCH₂Cl₂: Methylene chloride CHCl₃: Chloroform DMF: DimethylformamideDMSO: Dimethylsulfoxide EtOAc: Ethyl acetate HCl: Hydrcholric acid LiTMPLithium Tetramethylpiperidide MeCN: Acetonitrile MTBE: t-Butyl methylether NaBH₄: Sodium Borohydride NaCl: Sodium chloride NaCN: Sodiumcyanide NaHCO₃: Sodium bicarbonate NaOH: Sodium hydroxide THF:Tetrahydrofuran

EXAMPLE 1

[0030]

[0031] Phenyl isonicotinamide (6.00 g) is charged to a 500 mLthree-necked flask equipped with N₂ line, a thermometer and a stirrerchip. THF (180 mL) is added to the powder and the solution is cooled to−60° C. 1.56 M n-BuLi in hexane (39.8 mL) is added dropwise keeping thetemperature below −55° C. After stirring at −60° C. for 2h, a solutionof 1,4-Cyclohexanedione-mono-ethylene ketal (5.67 g) in THF (30 mL) isadded dropwise to the resulting orange suspension below −58° C. and themixture is stirred for 1 h.

[0032] The reaction mixture is poured into H₂O (90 mL) and allowed towarm up to room temperature. The aqueous layer is separated andextracted with MTBE two times (60+30 mL). 5N HCl is added to the aqueouslayer to adjust the pH to 2.40 while maintaining the temperature below10° C. The aqueous solution is stirred for 20 h at 65° C. and thencooled to room temperature. After NaCl (23 g) is added, the solution isextracted with EtOAc (150 mL) and the organic layer is separated. Theaqueous layer is adjusted pH to 4.50 with 4.0 mL of 1N NaOH whilekeeping the temperature below 10° C. followed by extraction with EtOActwo times (70 mL+40 mL). Combined organic layer was washed with 5%NaHCO₃ aq (15 mL) and 20% NaCl aq (15 mL).

[0033] The organic layer is concentrated to 30 mL and then 5.3 mL of DMFis added. (The suspension is then warmed to 60° C. After the slurry isdissolved, the solution is cooled to 50° C. and stirred for 30 min. Theresulting slurry is then cooled to room temperature. Heptane (76 mL) isadded dropwise to the resulting slurry over 1h and the solution isstirred at 0° C. overnight.

[0034] The resulting crystals are filtered and washed with a mixedsolvent of EtOAc and heptane (1:5, 24 mL). The resulting wet cake isdried in a vacuum desiccator at 50° C. to yield the spriolactone.

[0035] The ketone (5.000 g, 23.02 mmol) is suspended in EtOH (40 mL).NaBH₄ (0.261 g, 6.90 mmol, 0.3 eqiv.) is suspended in EtOH (50 mL) in a200 mL 4-neck round bottomed flask and cooled to −30° C. The aboveslurry of ketone in EtOH is added to the NaBH₄ suspension in EtOH over20 min below −20° C. and the resulting slurry is stirred at −25˜-20° C.for 1 hrs.

[0036] 25%(w/w) aqueous NH₄Cl (15 mL) is added to the mixture over 5 minbelow −10° C. Subsequently the mixture is allowed to warm to roomtemperature and stirred at 20˜25° C. for 2 hrs (pH 8.3). EtOAc (150 mL),H₂O (25 mL) and 25% (w/w) aqueous NaCl (5 mL) are added to the slurry.After stirring for 5 min, the organic layer is separated and washed with25% (w/w) aqueous NaCl (25 mL). After separating, the NaCl aqueous layeris extracted with EtOAc (100 mL). The combined organic solution isconcentrated to 25 mL at 40° C. of the bath temperature under thereduced pressure. After adding H₂O (25 mL), the slurry is concentratedto 25 mL volume at 40° C. of the bath temperature under the reducedpressure. Then H₂O (20 mL) and EtOH (5 mL) is added and the batch isaged at 20-25° C. for 3 hrs. The crystals are filtered and washed withH₂O (15 mL). After drying in vacuo overnight at room temperature, theproduct is obtained as white crystals.

[0037] Alcohol (5 g, 22.8 mol) is charged to a 300 mL four-necked flask.THF (100 mL) is added to the powder and the resulting white suspensionis cooled to 0-5° C. using ice bath. To the white suspension, TEA (9.6mL, 68.4 mmol) is added dropwise. After stirring for 30 min, MsCl (2.7mL, 34.2 mmol) is added dropwise to the solution. The ice bath isremoved and the mixture is allowed to warm to room temperature (20 to25° C.) and stirred for 45 min. Water is added dropwise and EtOAc (50mL) is added. The water layer is removed, and organic layer isconcentrated to 30 mL in vacuo. DMF (16 mL) is added to the residue andthe solution is concentrated to 15 mL in vacuo. Water (5 mL) is addeddropwise to give slightly turbid solution. Additional water (75 mL) isadded dropwise and the resulting mixture is stirred for 10h. Thecrystals are filtered off, washed with H₂O (50 mL) and dried in vacuo.

[0038] A 2L four-necked round-bottomed flask, is charged with DMF (650ml, KF 100 ppm) and the Mesylate (65.0 g) under N₂ atmosphere. To theresulting solution, NaCN (12.9 g) is added at room temperature. Thesuspension is heated to 100° C. and stirred for 16h.

[0039] After being cooled to room temperature, H₂O (1300 ml) is addeddropwise to the solution with an ice-bath. The resulting suspension isstirred at room temperature for 2h and filtered. The pale-yellow solidis washed with H₂O (130 ml) and dried in vacuo (40° C.) to yield thenitrile.

[0040] A 1L four-necked round-bottomed flask is charged with H₂O (240ml) under N₂ atmosphere. To the H₂O, H₂SO₄ (99.3 ml) is added. Nitrileis added to the solution. The resulting suspension is warned to 100° C.and stirred for 16h.

[0041] After being cooled to room temperature, 4N NaOH (ca. 830 ml) isadded dropwise to the solution until pH is adjusted to 3˜3.5. Theresulting suspension is stirred at room temperature for 30 min andfiltered off. The pale-yellow solid is washed with H₂O (120 ml) anddried in vacuo (40° C.) to yield the carboxylic acid.

What is claimed is:
 1. A process for preparing a compound of formula I:

comprising the steps of: a. Combining a strong base with phenylisonicotinamide in an aprotic solvent; b. Adding a protected ketone; c.Adjusting the pH with an acid to between 1 and 4 to deprotect theketone; d. Treating the ketone with a reducing agent to provide analcohol; e. Activating the alcohol to make a leaving group; f.Displacing the leaving group with a cyanide to produce a nitrite; g.Hydrolyzing the nitrile with aqueous acid to produce the compound offormula I.
 2. The process of claim 1 wherein steps a. and b. are runbetween −78° C. and 0° C.
 3. The process of claim 2 wherein the aproticsolvent is selected from the group consisting of THF, toluene, heptane,dimethoxyethane, benzene, and hexane, diethyl ether, xylene, and anymixtures thereof.
 4. The process of claim 3 wherein the aprotic solventis THF.
 5. The process of claim 3 wherein the strong base is selectedfrom the group consisting of n-BuLi, sec-BuLi, t-BuLi, LiHMDS, NaHMDS,KHMDS and LiTMP.
 6. The process of claim 5 wherein the strong base isn-BuLi.
 7. The process of claim 5 wherein the protected ketone isselected from the group consisting of 1,4-cyclohexanedione-mono-ethyleneketal, dimethyl ketal, diethyl ketal, 1,3 dithiane and olefin.
 8. Theprocess of claim 7 wherein the acid is selected from the groupconsisting of hydrochloric, sulfuric, phosphoric, or triflic.
 9. Theprocess of claim 8 wherein the pH is adjusted to between 2 and
 3. 10.The process of claim 9 wherein the reducing agent is selected from thegroup consisting of sodium borohydride, lithium aluminum hydride, andDIBAL.
 11. The process of claim 10 wherein the leaving group is selectedfrom the group consisting of mesylate, tosylate, triflate, and halide.12. The process of claim 11 wherein the cyanide is selected from thegroup consisting of sodium cyanide, KCN, ZnCN2, and TMSCN.
 13. Theprocess of claim 12 wherein the aqueous acid is selected from the groupconsisting of sulfuric, hydrochloric, phosphoric, and any mixturesthereof.